Severe Spinal Cord Injury in Rats Induces Chronic Changes in the Spinal Cord and Cerebral Cortex Metabolism, Adjusted by Thiamine That Improves Locomotor Performance

Abstract

Our study aims at developing knowledge-based strategies minimizing chronic changes in the brain after severe spinal cord injury (SCI). The SCI-induced long-term metabolic alterations and their reactivity to treatments shortly after the injury are characterized in rats. Eight weeks after severe SCI, significant mitochondrial lesions outside the injured area are demonstrated in the spinal cord and cerebral cortex. Among the six tested enzymes essential for the TCA cycle and amino acid metabolism, mitochondrial 2-oxoglutarate dehydrogenase complex (OGDHC) is the most affected one. SCI downregulates this complex by 90% in the spinal cord and 30% in the cerebral cortex. This is associated with the tissue-specific changes in other enzymes of the OGDHC network. Single administrations of a pro-activator (thiamine, or vitamin B1, 1.2 mmol/kg) or a synthetic pro-inhibitor (triethyl glutaryl phosphonate, TEGP, 0.02 mmol/kg) of OGDHC within 15–20 h after SCI are tested as protective strategies. The biochemical and physiological assessments 8 weeks after SCI reveal that thiamine, but not TEGP, alleviates the SCI-induced perturbations in the rat brain metabolism, accompanied by the decreased expression of (acetyl)p53, increased expression of sirtuin 5 and an 18% improvement in the locomotor recovery. Treatment of the non-operated rats with the OGDHC pro-inhibitor TEGP increases the p53 acetylation in the brain, approaching the brain metabolic profiles to those after SCI. Our data testify to an important contribution of the OGDHC regulation to the chronic consequences of SCI and their control by p53 and sirtuin 5.

Daytime Dependence of the Activity of the Rat Brain Pyruvate Dehydrogenase Corresponds to the Mitochondrial Sirtuin 3 Level and Acetylation of Brain Proteins, All Regulated by Thiamine Administration Decreasing Phosphorylation of PDHA Ser293

“…Inhibiting the ERO1A pathway by either pharmacological or genetic means [ 45 , 46 ] reduces ROS production upon endoplasmic reticulum stress. Positive action of thiamine on metabolic adaptations and glutathione redox status in injured neural tissues [ 22 , 49 , 50 ] is thus in good agreement not only with the general metabolic action of thiamine as activator of oxidative glucose metabolism, but also with the thiamine-dependent downregulation of ERO1A in the rat brain shown in our current study ( Figure 3 ). These complex effects may contribute to beneficial action of pharmacological forms of thiamine in patients with neurodegenerative diseases [ 51 ].…”

“…The thiamine-dependent downregulation of the ERO1A level, observed independently of daytime ( Figure 3 ), is of particular interest also in view of neurodegeneration-causing events, which are stimulated by thiamine deficiency [ 48 ] and decreased by thiamine addition [ 22 , 49 , 50 , 51 ]. ERO1A is a FAD-dependent protein, which reoxidizes protein disulfide isomerases (such as PDIA1) and produces ROS (hydrogen peroxide), being involved in endoplasmic reticulum stress [ 44 , 52 ].…”

“…Thiamine is a precursor of the PDH coenzyme, thiamine diphosphate (ThDP), that is the major component of thiamine pool in most tissues [ 20 ]. In addition to this coenzyme role, thiamine and its derivatives regulate multiple protein targets by non-coenzyme binding which is observed not only among the enzymes metabolically linked to PDHC [ 13 , 21 , 22 ], but also among general regulators of oxidative metabolism, such as transcriptional factor p53 and PDH kinases [ 21 , 23 , 24 , 25 , 26 , 27 ]. In particular, ThDP may activate PDHC function directly (as a coenzyme), and indirectly (as an inhibitor of PDH kinases).…”

Physiological and Biochemical Markers of the Sex-Specific Sensitivity to Epileptogenic Factors, Delayed Consequences of Seizures and Their Response to Vitamins B1 and B6 in a Rat Model

“…In the study of the time-dependence of the vitamins effects, performed on the female rats only, the separate experimental groups received vitamins at varied intervals before the first PTZ administration, i.e., either 24 or 2 or 0.5 h, and after completion of a 45 min follow-up of the PTZ-induced seizures ( Supplementary Figure S1 ). This vitamin regimen took into account the results of previous studies on the potential protective effect of high doses of vitamins both before [ 72 ] and after [ 24 ] the exposure to stress, when increased availability of vitamins may provide better stabilization and normalization of the metabolic state, respectively [ 73 ]. Control animals received the injections with equivalent volumes of physiological solution (0.9% NaCl).…”

“…To characterize the molecular mechanisms and pathways involved, the physiological assessment is combined with the analysis of the consequences of a seizure for the brain biochemistry. In this part, the vitamin-dependent enzymes crucial for the brain metabolism of glutamate and GABA [ 1 , 2 , 22 , 23 , 24 , 25 , 26 ] are assayed, and the brain amino acid profiles [ 23 , 24 ] are quantified. As a result, we reveal sex differences in the sensitivity to PTZ administration, the biochemical markers of such differences and a dual sex-specific effect of the administration of vitamins B1 and B6 on a seizure associated with the regulation of the brain PLK activity.…”